Panel Endorses New Blood Thinner for Afib Patients

SILVER SPRING, Md. -- An FDA advisory panel has voted unanimously to recommend approval of the investigational anticoagulant dabigatran to reduce the risk of stroke and non-CNS systemic embolism in patients with atrial fibrillation.

The Cardiovascular and Renal Drugs Advisory Committee on Monday voted 9 to 0 that dabigatran works at least as well as the popular blood thinner warfarin. However, because dabigatran doesn't require laboratory monitoring, it doesn't present some of the same issues that make warfarin notoriously difficult to use.

The positive vote was no surprise: FDA reviewers last week released a glowing review of dabigatran, made by Boehringer Ingelheim, and recommended approval of the drug.

The panel based its decision on the 18,000-person, randomized, noninferiority RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which compared unblinded warfarin administration with blinded administration of two doses of dabigatran (110 mg and 150 mg).

A year ago, the RE-LY investigators reported that a 150-mg dose of dabigatran twice daily was more effective in preventing strokes in high-risk patients than warfarin, while a lower dose -- 110 mg -- was comparable to warfarin.

Compared with warfarin-treated subjects, the hazard ratio was 0.66 (with a 95% CI from 0.53 to 0.82; P<0.003 for superiority) in the dabigatran 150-mg arm and 0.91 (with a 95% CI from 0.74 to 1.11; P<0.0001 for noninferiority) in the dabigatran 110-mg arm.

"[The company] demonstrated that [the 150-mg dose] is superior to warfarin," said panelist Scott Emerson, a biostatistician at the University of Washington in Seattle. "If I had to take one or the other, I'd probably go with this."

As with warfarin, bleeding is the top safety concern with dabigatran. In RE-LY, the 110-mg dose of dabigatran was associated with less bleeding than warfarin, while the 150-mg dose was associated with about the same bleeding risks, although the bleeds tended to be less serious than those seen with warfarin.

Boehringer Ingelheim has suggested that the drug's label recommend a 150-mg dose, but stated that for patients at a high risk of bleeding, a 110-mg dose should be considered. The FDA reviewers disagreed with that assessment, because the larger dose was statistically superior to warfarin, whereas the smaller dose was just noninferior to warfarin.

The panel, however, was split on whether the FDA should approve two doses.

Steven Nissen, MD, a cardiologist at the Cleveland Clinic, was one of the five committee members who favored approving both doses. He said offering two dosing options might translate into wider use of the drug, and thus a greater number of strokes would be prevented in atrial fibrillation patients.

"I think if you don't have a 110-mg dose, we're not going to end up having more people treated," Nissen said. "I want more patients treated because stroke is such a devastating consequence."

Statistically, the higher dose is more effective, but it's better to treat atrial fibrillation patients with something than with nothing at all, he said, adding that he thinks often atrial fibrillation goes untreated because physicians fear causing more harm than good.

"In the mind of the physician, if they give them warfarin and they have an intracranial hemorrhage, [the physician] feels terrible. If [the physician] doesn't give them warfarin and they have a stroke, then that's just 'unlucky.'"

However, other panelists were uneasy about endorsing both doses when the data showed the higher dose was better at preventing stroke.

All panelists favored making it clear on the label that the best stroke-prevention results in the trial were seen in patients given the 150-mg doses.

Researchers recently presented a post-hoc analysis of RE-LY at the European Society of Cardiology meeting in Stockholm that found dabigatran may be an ideal anticoagulant for atrial fibrillation patients, especially those in centers that are less adept at managing patients taking warfarin. And at the European Society of Cardiology meeting in 2009, some predicted that dabigatran could replace warfarin as the standard treatment for atrial fibrillation.

Nissen told MedPage Today that it would be "huge" if the FDA approved dabigatran.

However, panelist Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Heart Institute in Los Angeles, said in order for that to happen, "the price has to be right."

Panelist aren't supposed to factor cost of a drug into their deliberations for the FDA, but Kaul told MedPage Today after the meeting that the dabigatran could be priced at between $8 and $12 per day, which is significantly more costly than warfarin.

A separate area of concern -- mentioned in the FDA briefing documents -- was an unexplained finding of RE-LY: that myocardial infarction rates were higher on dabigatran compared with warfarin. A reviewer told the panel Monday that treating 1,000 subjects per year with dabigatran will cause two more myocardial infarctions than warfarin treatment would cause.

However, the panel wasn't too concerned with that possible problem.

The FDA is not required to follow the advice of its advisory committees, but it often does.

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